This invention relates generally to the field of medicinal chemistry and specifically, to compounds that inhibit the activity of glycogen synthase kinase 3 (GSK3).
Protein kinases and phosphatases regulate a wide range of events such as cell division, cell signaling, differentiation and metabolism. Regulation of these events is achieved by changing the phosphorylation status of specific amino acid (mainly serine, threonine, or tyrosine) in target protein sequences, which in turn, alters the function of these target proteins. Precise control of protein phosphorylation is thus fundamental to normal cellular behaviors.
Glycogen synthase kinase 3 (GSK3) is a proline-directed serine/threonine kinase. Woodgett, Trends Biochem Sci. 16:177-81 (1991). GSK3 consists of two isoforms, xcex1 and xcex2, and is constitutively active in resting cells, inhibiting glycogen synthase by direct phosphorylation. Upon insulin activation, GSK3 is inactivated, thereby allowing the activation of glycogen synthase and possibly other insulin-dependent events. Subsequently, it has been shown that GSK3 activity is inactivated by other growth factors or hormones, that, like insulin, signal through receptor tyrosine kinases (RTKs). Examples of such signaling molecules include IGF-1 and EGF. Saito et al., Biochem J., 303:27-31 (1994); Welsh et al., Biochem. J. 294:625-29 (1993); and Cross et al., Biochem. J., 303:21-26 (1994).
Inhibition of GSK3 will thus mimic the action of known growth factors and thus would be useful in the treatment of disorders in which signaling by these factors is inadequate. Accordingly, the identification of inhibitors of GSK3 would be highly desirable.
The present invention provides GSK3 inhibitors having the structure: 
wherein:
W and Y are atoms each independently selected from the group consisting of a nitrogen atom and an optionally substituted carbon atom, wherein at least one of W and Y is a nitrogen atom;
L is a divalent aliphatic radical selected from the group consisting of a linear divalent radical having from about 2 to about 5 backbone atoms, acyclic divalent radical having from about 3 to about 7 backbone atoms, and a hybrid divalent having a linear component, which has from about 1 to about 3 backbone atoms, bonded to a cyclic component, which has from about 3 to about 7 backbone atoms,
wherein each of said backbone atoms is selected from the group consisting of a carbon atom and a heteroatom,
wherein at least 1 of said backbone atoms is a carbon atom, and wherein from 1 to about 3 of said backbone atoms is optionally a heteroatom, and
wherein said divalent aliphatic radical is optionally substituted;
R2 is an optionally substituted aryl;
R4 and R6 are each independently selected from the group consisting of hydrogen, a halo, and R7,
wherein R7 is a monovalent radical selected from the group consisting of a lower alkyl, a cycloalkyl, an aryl, an aminoalkyl, an aminoarakyl, an aminocycloalkylaryl, an arylcarboxamidocycloalkylaralkyl, an arylcarboxamidocycloalkylaryl, an arylcarboxamidoalkylcycloalkyl, an arylcarboxamidoaryl, an arylcarboxamidoalkyl, an arylcarboxamidoaralkyl, an arylcarboxamidoalkoxyalkyl, an aminoalkoxyalkyl, and an arylsulfamidoaralkyl, and
wherein R7 is optionally substituted;
R5 is selected from the group consisting of hydrogen, carboxyl, nitro, amino, cyano, an optionally substituted lower alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted aminoalkyl, an optionally substituted aminoaryl, an optionally substituted aminoaralkyl, an optionally substituted aminoalkoxyalkyl, an optionally substituted arylaminoalkyl, an optionally substituted arylaminoaryl, an optionally substituted arylaminoaralkyl, an optionally substituted arylalkylamino, an optionally substituted arylalkylaminoalkyl, an optionally substituted arylalkylaminoaralkyl, an optionally substituted carboxcycloamido, an optionally substituted acyloxyalkyl, an optionally substituted acyloxyaryl, an optionally substituted acyloxyaralkyl, an optionally substituted acyloxyalkylcycloalkyl, an optionally substituted acyloxyalkylaminoalkyl, and an optionally substituted sulfonylalkyl, an optionally substituted carbamylallyl, an optionally substituted carbamylaryl, an optionally substituted carbamylarakyL, an optionally substituted carbamylalkylamino, an optionally substituted carbamylalkylaminoalkyl, an optionally substituted carbamylalkylaminoaryl and an optionally substituted carbamylalkylaminoaralkyl;
wherein, no more than two of R4, R4, and R6 are hydrogen;
and salts thereof.
The present invention also provides GSK3 inhibitors having the structure: 
wherein:
W and Y are atoms each independently selected from the group consisting of a nitrogen atom and an optionally substituted carbon atom, wherein at least one of W and Y is a nitrogen atom;
L is a divalent aliphatic radical selected from the group consisting of a linear divalent radical having from 2 to about 5 backbone atoms, a cyclic divalent radical having from about 3 to about 7 backbone atoms, and a hybrid divalent radical having a linear component, which has from about 1 to about 3 backbone atoms, bonded to a cyclic component, which as from about 3 to about 7 backbone atoms,
wherein each of said backbone atoms is selected from the group consisting of a carbon atom and a heteroatom,
wherein at least 1 of said backbone atoms is a carbon atom,
wherein 2 or 3 backbone atoms in said linear divalent radical are heteroatoms,
wherein from 1 to about 3 of said backbone atoms in said cyclic divalent radical and said hybrid divalent radical are optionally heteroatoms, and
wherein said divalent aliphatic radical is optionally substituted;
R2 is an optionally substituted aryl;
R4 and R6 are each independently selected from the group consisting of hydrogen, a halo, and R7,
wherein R7 is a monovalent radical selected the group consisting of a lower alkyl a cycloalkyl, an aryl, an aminoalkyl, an aminoaralkyl, an aminocycloalkylaryl, an arylcarboxamidocycloalkylarlkyl, an arylcarboxamidocycloalkylaryl, an arylcarboxamidoallylcycloalkyl an arylcarboxamidoaryl an arylcarboxamidoalkyl, an arylcarboxamidoaralkyl, an arylcarboxamidoalkoxyalkyl, an aminoalkoxyalkyl, and an arylsulfamidoaralkyl and
wherein R7 is optionally substituted;
R15 is selected from the group consisting of carboxamido, an optionally substituted carboxamidoalkyl, an optionally substituted carboxamidoaryl, an optionally substituted carboxamidoaralkyl an optionally substituted carboxamidoalkylcarboxamido, an optionally substituted carboxamidoalkylcarboxamidoalkyl, an optionally substituted carboxamidoalkylcarboxamidoaryl, and an optionally substituted carboxamidoalkylcarboxamidoaralkyl;
wherein no more than two of R4, R15, and R6 are hydrogen; and salts thereof.
In yet another embodiment, the present invention provides a method for inhibiting GSK3 activity, said method comprising:
(i) providing an effective amount of GSK3 inhibitor compound (I) or (II); then
(ii) administering said effective amount of said GSK3 inhibitor compound to a subject.
In still a further embodiment, the present invention provides a method for treating a GSK3-mediated disorder, said method comprising:
(i) providing therapeutically effective amount of GSK3 inhibitor compound (I) or (II); then
(ii) administering to a subject said therapeutically effective amount of the GSK3 inhibitor compound, wherein said subject is afflicted with a GSK3-mediated disorder.